Thromboxane Receptor Antagonists in AERD/Asthma

ABSTRACT

The present invention is directed to methods of treating AERD (aspirin exacerbated respiratory disease) and/or asthma via the administration of a thromboxane receptor antagonist to a patient in need thereof.

FIELD OF THE INVENTION

The present invention is related to the use of thromboxane receptorantagonists (e.g., Ifetroban) in the treatment of AERD (aspirinexacerbated respiratory disease) and asthma; and pharmaceuticalcompositions for the treatment of the same.

BACKGROUND OF THE INVENTION

Aspirin Exacerbated Respiratory Disease (AERD) is a chronic medicalcondition that consists of asthma, recurrent sinus disease with nasalpolyps, as well as a sensitivity to aspirin and other non-steroidalanti-inflammatory drugs (NSAIDs). Patients suffering from typicallydevelop reactions triggered by aspirin or other NSAIDs. These reactionsinclude, but are not limited to increased nasal congestion orstuffiness; eye watering or redness; cough, wheezing, or chesttightness; frontal headache or sensation of sinus pain; flushing and/ora rash; nausea and/or abdominal cramping; and a general feeling ofmalaise, sometimes accompanied by dizziness.

From a scientific perspective, AERD is characterized by mast cellactivation with overproduction of cysteinyl leukotrienes followinginhibition of COX-1 by medications like aspirin or NSAIDs. The cause ofthe mast cell activation that occurs following COX-1 inhibition isunknown.

AERD affects about 10% of adults who have asthma. A large proportion(about 40%) of patients who have asthma and nasal polyps are sensitiveto aspirin and NSAIDs.

It is typical that human patients who are suffering from AERD also haveasthma, nasal congestion, and nasal polyps. Such patients often do notrespond to conventional treatments.

AERD is also commonly referred to as Samter's Triad or Aspirin SensitiveAsthma.

The most common treatment currently available for AERD is aspirindesensitization. Aspirin desensitization may be accomplished, forexample, by hospitalizing the patient and instituting a regimen whereinthe patient is initially given a very low dose (20-40 mg) of aspirin,with gradual higher doses given every 1.5-3 hours. Following anaspirin-induced reaction (and subsequent stabilization of the patient),further doses of aspirin are administered. The desensitization isconsidered to be complete once the patient has received a 325 mg dose ofaspirin without further reaction. The patient is then discharged andcontinues treatment with aspirin (typically either 325mg or 650 mg twicedaily). However, aspirin desensitization does not help many AERDpatients.

Other treatments include an antibiotic such as tobramycin or biaxin, asalicylate-free diet, a corticosteroid such as betamethasone, and/oracetylcysteine.

Aspirin challenge of subjects with aspirin exacerbated respiratorydisease (AERD) results in the activation of mast cells (MCs), asevidenced by increases in the levels of tryptase in both serum (Bochenek2003) and nasal lavage fluid (Fischer 1994). In addition, the levels of9α-11β-PGF2, a PGD2 metabolite, increase in the plasma during thereaction to aspirin (Bochenek 2003). PGD2 has been shown to activate thethromboxane prostanoid (TP) receptors found on bronchial smooth musclethereby causing bronchoconstriction (Armour 1989; Bochenek 2003;Pettipher 2007). Administration of ifetroban in vitro has been shown toinhibit contraction of guinea pig trachea elicited by PGD2 (Ogletree1992) and to both preempt and reverse TP receptor-induced bronchospasmin rats and guinea pigs. Direct endobronchial application of lysine-aspirin does not decrease the levels of PGD2 and PGD2 metabolitesrecovered from bronchoalveolar lavage (BAL) fluids from AERD patients.However, endobronchial application of lysine-aspirin does reduce theconcentration of other prostaglandins (Sladek 1994; Szczeklik 1996).Thus, PGD2 production in AERD resists suppression by aspirin.

The expression of COX-2, a relatively aspirin-resistant enzyme, isexpressed by a larger percentage of MCs in bronchial biopsies frompatients with AERD than in those of aspirin tolerant controls (Sousa1997). Since global expression of COX-2 in nasal polyps is reduced inAERD relative to aspirin-tolerant controls (Picado 1999), the selectiveupregulation of COX-2 expression by MCs likely reflects cell-specificdifferences in the regulation of the COX-2 isoform. Thus, the capacityfor MCs to release PGD2 in AERD during aspirin challenge may be due totheir preferential utilization of COX-2 for this function. The capacityof PGD2 to recruit and activate immune effector cells, inducevasodilation, and cause bronchoconstriction would fit well with a rolein the pathophysiology of AERD, especially since its production resistssuppression by low-dose aspirin.

Human studies demonstrate markedly impaired COX-2-dependent synthesis ofPGE2 in the sinonasal tissues of patients with AERD compared withaspirin-tolerant controls (Picado 1999; Yoshimura 2008). Previousclinical studies also strongly support a critical role ofplatelet-adherent granulocytes as a source of cysteinyl leukotrienes(cys-LTs) in human subjects with AERD (Laidlaw 2012). To further explorethe pathogenetic consequences of a deficit in COX-2-dependent PGE2generation, sustained PGD2 generation, and the role of platelets inAERD, mice lacking microsomal PGE2 synthase (ptges−/− mice) weredeveloped (Liu 2012; Liu 2013). PGE2 synthase is the dominant terminalenzyme responsible for conversion of COX-2-derived PGH2 to PGE2(Murakami 2000).

To elicit the AERD phenotype in the ptges−/− mice, six doses of anextract of allergens from the house dust mite Dermatophagoides farina(Df) were administered and the animals developed marked eosinophilicbronchovascular inflammation compared with WT controls (Liu 2012). Theblood and lungs of ptges−/− mice contained markedly increased numbers ofplatelets adhering to granulocytes, similar to the findings in humans.When challenged by inhalation of Lysine aspirin, Df-treated ptges−/−mice exhibited significant increases in airway resistance, accompaniedby increases in the levels of cys-LTs, histamine, and mouse MC protease1 in the BAL fluid. The increase in airway resistance was sensitive tointerference by zileuton or montelukast (Liu 2013), consistent with theknown pharmacology of AERD in humans. Exogenous antibody-mediatedplatelet depletion prior to the Lys-ASA challenge completely eliminatedthe increases in airway resistance and cys-LTs. Moreover, deletion of TPreceptors from ptges−/− mice or the administration of SQ29,548, aselective antagonist of the TP receptor, completely blocked the reactionto aspirin and the rise in cys-LTs (FIG. 1). These findings imply thatsignaling through TP receptors is critical for platelets to mediate thetranscellular synthesis of leukotriene C4 (LTC4) during challenge withaspirin. These observations support the hypothesis that TP receptorblockade will reduce the synthesis of cys-LTs in AERD and therebyprovide a new treatment modality for the disease and ease thedesensitization to aspirin.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide new methods oftreating AERD and/or asthma.

It is an object of the invention to reduce rescue medications needed asa result of an aspirin-induced reaction in a human patient sufferingfrom AERD.

It is another object of the invention to reduce the symptoms of aspirindesensitization in AERD patients.

It accordance with the above object and others, the present invention isdirected in part to providing a method of treating and/or preventingAERD or asthma in human patients by administration of a therapeuticallyeffective amount of a thromboxane receptor antagonist. Preferably, thetherapeutically effective amount of thromboxane receptor antagonist issufficient to provide a plasma concentration of the thromboxane receptorantagonist of about 0.1 ng/ml to about 10,000 ng/ml, preferably fromabout 1.0 ng/ml to about 6000 ng/ml, or from about 40 ng/ml to about3500 ng/ml, or from about 300 ng/ml to about 2500 ng/ml.

In certain embodiments, the thromoboxane receptor antagonist is athromboxane A₂ receptor antagonist to a human patient(s). In preferredembodiments, the thromboxane A₂ antagonist is[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid (Ifetroban), or pharmaceutically acceptable salts thereof Incertain preferred embodiments, the thromboxane A₂ receptor antagonist isifetroban or a pharmaceutically acceptable salt thereof (e.g., ifetrobansodium) and the dose administered orally to human patients is from aboutin a daily dose from about 25 mg to about 400 mg. In such embodiments,the patient(s) will (preferably) require a reduced amount of rescuemedications as compared to human patients who are not administeredifetroban. In certain preferred embodiments, the ifetroban isadministered orally in an amount from about 150 mg to about 400 mg, fromabout 200 mg to about 300 mg, and in certain embodiments most preferablyabout 200 mg. In certain preferred embodiments, the ifetroban isifetroban sodium.

The present invention is further directed in part to providing a methodfor treating and/or preventing AERD or asthma by administration of atherapeutically effective amount of [1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, monosodium salt (Ifetroban Sodium) to a human patient(s).Preferably, the therapeutically effective amount provides a plasmaconcentration of the Ifetroban of about 0.1 ng/ml to about 10,000 ng/ml,preferably from about 1.0 ng/ml to about 6000 ng/ml, or from about 40ng/ml to about 3500 ng/ml, or from about 300 ng/ml to about 2500 ng/ml.In certain preferred embodiments, the thromboxane A₂ receptor antagonistis ifetroban or a pharmaceutically acceptable salt thereof (e.g.,ifetroban sodium) and the dose administered orally to human patients isfrom about in a daily dose from about 25 mg to about 400 mg. In suchembodiments, the patient(s) will (preferably) require a reduced amountof rescue medications as compared to human patients who are notadministered ifetroban. In certain preferred embodiments, the ifetrobanis administered orally in an amount from about 150 mg to about 400 mg,from about 200 mg to about 300 mg, and in certain embodiments mostpreferably about 200 mg. In certain preferred embodiments, the ifetrobanis ifetroban sodium.

In accordance with the above objects, the present invention provides formethods of preventing, reversing or treating a symptom associated withAERD or asthma including but not limited to nasal congestion (orstuffiness), eye watering, eye redness, coughing, wheezing, chesttightness; frontal headache, sensation of sinus pain, flushing, rash,hives, nausea, abdominal cramping, a general feeling of malaise,dizziness, difficulty breathing, and combinations of any of theforegoing by the administration of a therapeutically effective amount ofa thromboxane receptor antagonist (preferably, a thromboxane A₂ receptorantagonist) to a patient in need thereof In certain preferredembodiments, the therapeutically effective amount of a thromboxane A₂receptor antagonist provides a plasma concentration of the thromboxaneA₂ receptor antagonist of about 0.1 ng/ml to about 10,000 ng/ml, whereinthe desired plasma concentration results in the patient experiencing alessening of said symptom(s). In preferred embodiments, the thromboxaneA₂ antagonist is[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid (Ifetroban), or pharmaceutically acceptable salts thereof. Inanother preferred embodiment, the thromboxane receptor antagonist is[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, monosodium salt (Ifetroban Sodium). In certain preferredembodiments, the thromboxane A₂ receptor antagonist is ifetroban or apharmaceutically acceptable salt thereof (e.g., ifetroban sodium) andthe dose administered orally to human patients is from about 150 mg/dayto about 400 mg/day, administered in one dose or divided doses. Incertain preferred embodiments, the thromboxane A₂ receptor antagonist isifetroban sodium and the dose is about 200 mg/day when administeredorally to a human patient(s) suffering from AERD and/or asthma.

The invention is also directed in part to a method of reducing rescuemedications as a result of an aspirin-induced reaction in a humanpatient(s) suffering from AERD, comprising administering ifetroban or apharmaceutically acceptable salt thereof in a daily dose from about 25mg to about 400 mg. In such embodiments, the patient(s) will(preferably) require a reduced amount of rescue medications as comparedto human patients who are not administered ifetroban. In certainpreferred embodiments, the ifetroban is administered orally in an amountfrom about 150 mg to about 400 mg, from about 200 mg to about 300 mg,and in certain embodiments most preferably about 200 mg. In certainpreferred embodiments, the ifetroban is ifetroban sodium.

The invention is also directed in part to a method of reducing thesymptoms of aspirin desensitization in a human AERD patient(s),comprising rescue medications as a result of an aspirin-induced reactionin a human patient(s) suffering from AERD, comprising orallyadministering ifetroban or a pharmaceutically acceptable salt thereof ina daily dose from about 25 mg to about 400 mg. In such embodiments, thepatient(s) will (preferably) require a reduced amount of rescuemedications as compared to human patients who are not administeredifetroban. In certain preferred embodiments, the ifetroban isadministered orally in an amount from about 150 mg to about 400 mg, fromabout 200 mg to about 300 mg, and in certain embodiments most preferablyabout 200 mg. In certain preferred embodiments, the ifetroban isifetroban sodium.

In any of the above methods, the thromboxane A₂ receptor antagonist maybe ifetroban or a pharmaceutically acceptable salt thereof (e.g.,ifetroban sodium) in a daily dose of about 25 mg, about 50 mg, about 75mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325mg, about 350 mg, about 375 mg, and about 400 mg. The daily dose may beadministered once daily, twice daily, three times daily, or four timesdaily.

The phrase “therapeutically effective amount” refers to that amount of asubstance that produces some desired local or systemic effect at areasonable benefit/risk ratio applicable to any treatment. The effectiveamount of such substance will vary depending upon the subject anddisease condition being treated, the weight and age of the subject, theseverity of the disease condition, the manner of administration and thelike, which can readily be determined by one of ordinary skill in theart.

The term “thromboxane A₂ receptor antagonist” as used herein refers to acompound that inhibits the expression or activity of a thromboxanereceptor by at least or at least about 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% in astandard bioassay or in vivo or when used in a therapeutically effectivedose. In certain embodiments, a thromboxane A₂ receptor antagonistinhibits binding of thromboxane A₂ to the receptor. Thromboxane A₂receptor antagonists include competitive antagonists (i.e., antagoniststhat compete with an agonist for the receptor) and non-competitiveantagonists. Thromboxane A₂ receptor antagonists include antibodies tothe receptor. The antibodies may be monoclonal. They may be human orhumanized antibodies. Thromboxane A₂ receptor antagonists also includethromboxane synthase inhibitors, as well as compounds that have boththromboxane A₂ receptor antagonist activity and thromboxane synthaseinhibitor activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the deletion or blockade of TP receptors attenuatesaspirin sensitivity in PGE2-deficient mice. (A) Peak change in RLoccurring in response to Lys-ASA challenge of ptges−/− or ptges/tpr−/−(DKO) mice 24 h after their final treatment with PBS or Df. (B) Peakchange in RL in ptges−/− mice receiving two doses of the TP receptorselective antagonist SQ29.548 prior to challenge with Lys-ASA. (C)Levels of cys-LTs, mMCP-1, and histamine in BAL fluids from the samemice as in (B). Results are from 10 mice/group. (Adapted from Liu 2013).

DETAILED DESCRIPTION OF THE INVENTION

The discovery and development of thromboxane A₂ receptor antagonists hasbeen an objective of many pharmaceutical companies for approximately 30years (see, Dogne J-M, et al., Exp. Opin. Ther. Patents 11: 1663-1675(2001)). Certain individual compounds identified by these companies,either with or without concomitant thromboxane A₂ synthase inhibitoryactivity, include ifetroban (BMS), ridogrel (Janssen), terbogrel (BI),UK-147535 (Pfizer), GR 32191 (Glaxo), and S-18886 (Servier). Preclinicalpharmacology has established that this class of compounds has effectiveantithrombotic activity obtained by inhibition of the thromboxanepathway. These compounds also prevent vasoconstriction induced bythromboxane A₂ and other prostanoids that act on the thromboxane A₂receptor within the vascular bed, and thus may be beneficial for use inpreventing and/or treating hepatorenal syndrome and/or hepaticencephalopathy.

Suitable thromboxane A₂ receptor antagonists for use in the presentinvention may include, for example, but are not limited to smallmolecules such as ifetroban (BMS;[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(pentylamino)carbony-1]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2yl]methyl]benzenepropanoic acid), as well as others described in U.S.Patent Application Publication No. 2009/0012115, the disclosure of whichis hereby incorporated by reference in its entirety.

Additional thromboxane A₂ receptor antagonists suitable for use hereinare also described in U.S. Pat. No. 4,839,384 (Ogletree); U.S. Pat. No.5,066,480 (Ogletree, et al.); U.S. Pat. No. 5,100,889 (Misra, et al.);U.S. Pat. No. 5,312,818 (Rubin, et al.); U.S. Pat. No. 5,399,725 (Poss,et al.); and U.S. Pat. No. 6,509,348 (Ogletree), the disclosures ofwhich are hereby incorporated by reference in their entireties. Thesemay include, but are not limited to, interphenylene 7-oxabicyclo-heptylsubstituted heterocyclic amide prostaglandin analogs as disclosed inU.S. Pat. No. 5,100,889, including:

[1S-(1α, 2α, 3α,4α)]-2-[[3-[4-[[(4-cyclo-hexylbutyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]-hept-2-yl]methyl]benzenepropanoicacid (SQ 33,961), or esters or salts thereof;

[1S-(1α, 2α, 3α, 4α)] -2- [[3-[4-[[[(4-chloro- phenyl)-butyl] amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acidor esters, or salts thereof;

[1S-(1α, 2α, 3α,4α)]-[3-[[3-[4-[[(4-cycloh-exylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo]2.2.1]hept-2-yl]benzeneacetic acid, or esters or salts thereof;

[1S-(1α, 2α, 3α,4α)]-[2-[[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]phenoxy]aceticacid, or esters or salts thereof;

[1S-(1α, 2α, 3α, 4α]-2-[[3-[4-[[(7,7-dime-thyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-methyl]benzenepropanoicacid, or esters or salts thereof.

7-oxabicycloheptyl substituted heterocyclic amide prostaglandin analogsas disclosed in U.S. Pat. No. 5,100,889, issued Mar. 31, 1992, including[1S-[1α, 2α (Z), 3α, 4α)]-643-[4-[[(4-cyclohexylbutyl)amino] -carbonyl]-2-oxazolyl] -7-oxabicyclo [2.2.1] hept-2-yl] -4-hexenoic acid, oresters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-thiazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)methylamino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[(1-pyrrolidinyl)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[(cyclohexylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl-4-hexenoicacid or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[(2-cyclohexyl-ethyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[[2-(4-chloro-phenyl)ethyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]-6-[3-[4-[[(4-chlorophenyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[[4-(4-chloro-phenyl)butyl]amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4.alpha.-[[-(6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters, or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[(6-cyclohexyl-hexyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α]]-6-[3-[4-[(propylamino)-carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[(4-butylphenyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[(2,3-dihydro-1H-indol-1-yl)carbonyl]-2-oxazolyl]-7-oxabicyclo(2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-N-(phenylsulfonyl)-4-hexenamide;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-N-(methylsulfonyl)-7-oxabicyclo[2-.2.1]hept-2-yl]-4-hexenamide;

[1S-[1α, 2α (Z), 3α,4α)]]-7-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo(2.2.1]hept-2-yl]-5-heptenoic acid, or esters or salts thereof;

[1S-[1α, 2α (Z), 3α,4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-1H-imidazol-2-yl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoicacid or esters or salts thereof;

[1S-[1α, 2α, 3α, 4α)]-6-[3-[4-[[(7,7-dimethyloctyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

[1S-[1α, 2α(E), 3α,4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid;

[1S-[1α, 2α, 3α,4α)]-3-[4-[[(4-(cyclohexylbutyl)-amino]carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]heptane-2-hexanoicacid or esters or salts thereof,

[1S-[1α, 2α(Z), 3α, 4α)]]-6-[3-[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-2-oxazolyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-4-hexenoicacid, or esters or salts thereof;

7-oxabicycloheptane and 7-oxabicycloheptene compounds disclosed in U.S.Pat. No. 4,537,981 to Snitman et al, the disclosure of which is herebyincorporated by reference in its entirety, such as [1S-(1α, 2α(Z),3α(1E, 3S*, 4R*),4α)]]-7-[3-(3-hydroxy-4-phenyl-l-pentenyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid (SQ 29,548); the 7-oxabicycloheptane substituted aminoprostaglandinanalogs disclosed in U.S. Pat. No. 4,416,896 to Nakane et al, thedisclosure of which is hereby incorporated by reference in its entirety,such as [1S-[1α, 2α(Z), 3α,4α)]]-7-[3-[[2-(phenylamino)carbonyl]-hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid; the 7-oxabicycloheptane substituted diamide prostaglandin analogsdisclosed in U.S. Pat. No. 4,663,336 to Nakane et al, the disclosure ofwhich is hereby incorporated by reference in its entirety, such as,[1S-[1α, 2α(Z), 3α,4α)]]-7-[3-[[[[(1-oxoheptyl)amino]-acetyl]amino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoicacid and the corresponding tetrazole, and [1S-[1α, 2α(Z),3α,4α)]]-7-[3-[[[[(4-cyclohexyl-1-oxobutyl)-amino]acetyl]amino]methyl]-7-oxabicyclo]2.2.1]hept-2-yl]-5-heptenoicacid;

7-oxabicycloheptane imidazole prostaglandin analogs as disclosed in U.S.Pat. No. 4,977,174, the disclosure of which is hereby incorporated byreference in its entirety, such as [1S-[1α, 2α(Z), 3α,4α)]]-6-[3-[[4-(4-cyclohexyl-1-hydroxybutyl)-1H-imidazole-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid or its methyl ester;

[1S-[1α, 2α(Z), 3α,4α)]]-6-[3-[[4-(3-cyclohexyl-propyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid or its methyl ester;

[1S-[1α, 2α(X(Z), 3α,4α)]]-6-[3-[[4-(4-cyclohexyl-1-oxobutyl)-1H-imidazol-1-yl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid or its methyl ester;

[1S-[1α, 2α(Z), 3α,4α]]-6-[3-(1H-imidazol-1-ylmethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-4-hexenoicacid or its methyl ester; or

[1S-[1α, 2α(Z), 3α,4α)]]-6-[3-[[4-[[(4-cyclohexyl-butyl)amino]carbonyl]-1H-imidazol-1-yl]methyl-7-oxabicyclo-[2.2.1]-hept-2-yl]-4-hexenoicacid, or its methyl ester;

The phenoxyalkyl carboxylic acids disclosed in U.S. Pat. No. 4,258,058to Witte et al, the disclosure of which is hereby incorporated byreference in its entirety, including4-[2-(benzenesulfamido)ethyl]phenoxy- acetic acid (BM 13,177-BoehringerMannheim), the sulphonamidophenyl carboxylic acids disclosed in U.S.Pat. No. 4,443,477 to Witte et al, the disclosure of which is herebyincorporated by reference in its entirety, including4-[2-(4-chlorobenzenesulfonamido)ethyl]-phenylacetic acid (BM 13,505,Boehringer Mannheim), the arylthioalkylphenyl carboxylic acids disclosedin U.S. Pat. No. 4,752,616, the disclosure of which is herebyincorporated by reference in its entirety, including4-(3-((4-chlorophenyl)sulfonyl)propyl)benzene acetic acid.

Other examples of thromboxane A₂ receptor antagonists suitable for useherein include, but are not limited to vapiprost (which is a preferredexample),(E)-5-[[[(pyridinyl)]3-(trifluoromethyl)phenyl]methylene]amino]-oxy]pentanoicacid also referred to as R68,070-Janssen Research Laboratories,3-[1-(4-chlorophenylmethyl)-5-fluoro-3-methylindol-2-yl]-2,-2-dimethylpropanoicacid [(L-655240 Merck-Frosst) Eur. J. Pharmacol. 135(2):193, Mar. 17,87],5(Z)-7-([2,4,5-cis]-4-(2-hydroxyphenyl)-2-trifl-uoromethyl-1,3-dioxan-5-yl)heptenoicacid (ICI 185282, Brit. J. Pharmacol. 90 (Proc. Suppl):228 P-Abs, March87), 5(Z)-7-[2,2-dimethyl-4-phenyl-1,3-dioxan-cis-5-yl]heptenoic acid(ICI 159995, Brit. J. Pharmacol. 86 (Proc. Suppl):808 P-Abs., December85),N,N′-bis[7-(3-chlorobenzeneamino-sulfony-l)-1,2,3,4-tetrahydro-isoquinolyl]disulfonylimide(SKF 88046, Pharmacologist 25(3):116 Abs., 117 Abs, August 83),(1.alpha.(Z)-2.beta.,5.alpha.]-(+)-7-[5-[[(1,1′-biphenyl)-4-yl]-methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoicacid (AH 23848 -Glaxo, Circulation 72(6):1208, December 85, levallorphanallyl bromide (CM 32,191 Sanofi, Life Sci. 31 (20-21):2261, Nov. 15,82), (Z,2-endo-3-oxo)-7-(3-acetyl-2-bicyclo[2.2.1]heptyl-5-hepta-3Z-enoic acid, 4-phenyl-thiosemicarbazone(EP092-Univ. Edinburgh, Brit. J. Pharmacol. 84(3):595, March 85); GR32,191 (Vapiprost)-[1R-[1.alpha.(Z), 2.beta., 3.beta.,5.alpha.]]-(+)-7-[5-([1,1′-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoicacid; ICI192,605-4(Z)-6-[(2,4,5-cis)2-(2-chlorophenyl)-4-(2-hydroxyphenyl)-1,3-dioxan-5-yl]hexenoicacid; BAY u 3405(ramatroban)-3-[[(4-fluorophenyl)-sulfonyl]amino]-1,2,3,4-tetrahydro-9H-c-arbazole-9-propanoic acid; or ONO 3708-7-[2.alpha.,4.alpha.-(dimethylmethano)-6.beta.-(2-cyclopentyl-2.beta.-hydroxyacetami-do)-1.alpha.-cyclohexyl]-5(Z)-heptenoic acid;(.+−.)(5Z)-7-[3-endo-((phenylsulfonyl)amino]-bicyclo[2.2.1]hept-2-exo-yl]-heptenoicacid (S-1452, Shionogi domitroban, Anboxan®.);(−)6,8-difluoro-9-p-methylsulfonylben-zyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid (L670596, Merck) and(3-[1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-yl]-2,2-dimethylpropanoicacid (L655240, Merck).

The preferred thromboxane A₂ receptor antagonist of the presentinvention is ifetroban or any pharmaceutically acceptable salts thereof.

In certain preferred embodiments the preferred thromboxane A₂ receptorantagonist is ifetroban sodium (known chemically as[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, monosodium salt.

In certain embodiments, the AERD and/or asthma is treated via theadministration of a thromboxane receptor antagonist (e.g., a thromboxaneA₂ receptor antagonist) ranging from about 0.1 ng/ml to about 10,000ng/ml. Preferably, the plasma concentration of thromboxane receptorantagonist ranges from about 1 ng/ml to about 1,000 ng/ml, preferablyfrom about 1.0 ng/ml to about 6000 ng/ml, or from about 40 ng/ml toabout 3500 ng/ml, or from about 300 ng/ml to about 2500 ng/ml.

In certain preferred embodiments, the thromboxane A₂ receptor antagonistis ifetroban or a pharmaceutically acceptable salt thereof (e.g.,ifetroban sodium) and the dose administered orally to human patients isfrom about 150 mg/day to about 400 mg/day, administered in one dose ordivided doses. In certain preferred embodiments, the thromboxane A₂receptor antagonist is ifetroban sodium and the dose is about 200 mg/daywhen administered orally to a human patient(s) suffering from AERDand/or asthma.

When the thromboxane A₂ receptor antagonist is ifetroban, the desiredplasma concentration for providing a therapeutic effect for thetreatment of AERD and/or asthma should be greater than about 10 ng/mL(ifetroban free acid). Some therapeutic effect of thromboxane A₂receptor antagonist, e.g., ifetroban, may be seen at concentrations ofgreater than about 1 ng/mL.

The dose administered must be carefully adjusted according to age,weight and condition of the patient, as well as the route ofadministration, dosage form and regimen and the desired result.

However, in order to obtain the desired plasma concentration ofthromboxane A₂ receptor antagonists, daily doses of the thromboxane A₂receptor antagonists ranging from about 0.1 mg to about 5000 mg shouldbe administered. Preferably, the daily dose of thromboxane A₂ receptorantagonists ranges from about 1 mg to about 1000 mg; about 10 mg toabout 1000 mg; about 50 mg to about 500 mg; about 100 mg to about 500mg; about 200 mg to about 500 mg; about 300 mg to about 500 mg; andabout 400 mg to about 500 mg per day.

In certain preferred embodiments, a daily dose of ifetroban sodium fromabout 10 mg to about 250 mg (ifetroban free acid amounts) will produceeffective plasma levels of ifetroban free acid.

The thromboxane A₂ receptor antagonists of the present invention may beadministered by any pharmaceutically effective route. For example, thethromboxane A₂ receptor antagonists may be formulated in a manner suchthat they can be administered orally, intranasally, rectally, vaginally,sublingually, buccally, parenterally, or transdermally, and, thus, beformulated accordingly.

In certain embodiments, the thromboxane A₂ receptor antagonists may beformulated in a pharmaceutically acceptable oral dosage form. Oraldosage forms may include, but are not limited to, oral solid dosageforms and oral liquid dosage forms.

Oral solid dosage forms may include, but are not limited to, tablets,capsules, caplets, powders, pellets, multiparticulates, beads, spheresand any combinations thereof. These oral solid dosage forms may beformulated as immediate release, controlled release, sustained(extended) release or modified release formulations.

The oral solid dosage forms of the present invention may also containpharmaceutically acceptable excipients such as fillers, diluents,lubricants, surfactants, glidants, binders, dispersing agents,suspending agents, disintegrants, viscosity-increasing agents,film-forming agents, granulation aid, flavoring agents, sweetener,coating agents, solubilizing agents, and combinations thereof.

Depending on the desired release profile, the oral solid dosage forms ofthe present invention may contain a suitable amount ofcontrolled-release agents, extended-release agents, modified-releaseagents.

Oral liquid dosage forms include, but are not limited to, solutions,emulsions, suspensions, and syrups. These oral liquid dosage forms maybe formulated with any pharmaceutically acceptable excipient known tothose of skill in the art for the preparation of liquid dosage forms.For example, water, glycerin, simple syrup, alcohol and combinationsthereof.

In certain embodiments of the present invention, the thromboxane A₂receptor antagonists may be formulated into a dosage form suitable forparenteral use. For example, the dosage form may be a lyophilizedpowder, a solution, suspension (e.g., depot suspension).

In other embodiments, the thromboxane receptor antagonists may beformulated into a topical dosage form such as, but not limited to, apatch, a gel, a paste, a cream, an emulsion, liniment, balm, lotion, andointment.

A significant proportion of patients that suffer from asthma take one ormore medications on a daily (chronic) basis in order to prevent orattenuate symptoms of asthma. Such drugs include corticosteroids(including but not limited to inhaled corticosteroids), Cromolyn,Omalizumab, short or long-acting beta-2 agonists (typically inhaled),leukotriene modifiers (e.g., zafirlukast (Accolate®), montelukast(Singulair®), and zileuton (Zyflo®)), and theophylline. Advair (acombination drug that includes a steroid and a long-actingbronchodilator drug). Inhaled steroid medications include but are notlimited to the following: Aerobid®, Asmanex®, Azmacort®, Dulera® (acombination drug that also includes a long-acting bronchodilator drug),Flovent®, Pulmicort®, Symbicort® (a combination drug that includes asteroid and a long-acting bronchodilator drug), Qvar®, and the like.Inhaled steroids come in three forms: the metered dose inhaler (MDI),dry powder inhaler (DPI), and nebulizer solutions. Omalizumab (tradename Xolair®, Roche/Genentech and Novartis) is a humanized antibodyoriginally designed to reduce sensitivity to inhaled or ingestedallergens, especially in the control of moderate to severe allergicasthma, which does not respond to high doses of corticosteroids. Incertain embodiments, the present method of treatment furthercontemplates combination therapy comprising administering a thromboxanereceptor antagonist and one or more of the above drugs to a humanpatient suffering from AERD and/or asthma.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples are not meant to be limiting and representcertain embodiments of the present invention.

Example 1

In this example, ifetroban sodium tablets are prepared with thefollowing ingredients listed in Table 1:

TABLE 1 Ingredients Percent by weight Na salt of Ifetroban 35 Mannitol50 Microcrystalline Cellulose 8 Crospovidone 3.0 Magnesium Oxide 2.0Magnesium Stearate 1.5 Colloidal Silica 0.3

The sodium salt of ifetroban, magnesium oxide, mannitol,microcrystalline cellulose, and crospovidone is mixed together for about2 to about 10 minutes employing a suitable mixer. The resulting mixtureis passed through a #12 to #40 mesh size screen. Thereafter, magnesiumstearate and colloidal silica are added and mixing is continued forabout 1 to about 3 minutes.

The resulting homogeneous mixture is then compressed into tablets eachcontaining 35 mg, ifetroban sodium salt.

Example II

In this example, 1000 tablets each containing 400 mg of Ifetroban sodiumare produced from the following ingredients listed in Table 2:

TABLE 2 Ingredients Amount Na salt of Ifetroban  400 gm Corn Starch 50 gGelatin 7.5 g  Microcrystalline Cellulose (Avicel) 25 g MagnesiumStearate 2.5 g 

Example III

In this example. An injectable solution of ifetroban sodium is preparedfor intravenous use with the following ingredients listed in Table 3:

TABLE 3 Ingredients Amount Ifetroban Sodium 2500 mg Methyl Paraben 5 mgPropyl Paraben 1 mg Sodium Chloride 25,000 mg Water for injection q.s. 5liter

The sodium salt of ifetroban, preservatives and sodium chloride aredissolved in 3 liters of water for injection and then the volume isbrought up to 5 liters. The solution is filtered through a sterilefilter and aseptically filled into pre-sterilized vials which are thenclosed with pre-sterilized rubber closures. Each vial contains aconcentration of 75 mg of active ingredient per 150 ml of solution.

Example IV

Example IV is a multicenter, double-blind, randomized,placebo-controlled trial to determine the safety of oral ifetroban inpatients with a history of aspirin exacerbated respiratory disease(AERD).

The eligible subjects were randomized (3:1 active to placebo) in this7-day study which consisted of a screening, treatment and follow-upperiod. Any subject receiving at least a partial dose of IMP were notreplaced and included in the study analysis. Of 19 subjects enrolled andrandomized to study treatment, 14 (74%) were randomized to the ifetrobangroup and 5 (26%) to the placebo group. Of those 14 randomized toifetroban, 12 (86%) subjects were treated and 100% of those treatedcompleted treatment. Of 5 subjects randomized to placebo, 4 (80%)started treatment and 100% completed treatment. All treated subjectswere analyzed for safety and efficacy variables.

A placebo treatment arm was included in this study to provide data onthe spontaneous response rate of AERD subjects, as well as to helpidentify any safety or efficacy signals in the subjects receivingifetroban. In numerous trials, subjects with asthma assigned to placebohave demonstrated improvement in symptoms, quality of life, and even inlung function, such as FEV1. In general, the placebo effect in asthmacan be as great as 30 to 50% depending on which endpoint is chosen(Castro, 2007; Placebo versus Best-Available-Therapy Control Group inClinical Trials for Pharmacologic Therapies. Proceedings of the AmericanThoracic Society, 570-573).

All individuals with AERD will experience a clinical reaction toaspirin, most often at a dose of 81 mg or below. By utilizing a modifiedScripps Institute protocol (Hope, Woessner, Simon, & Stevenson, 2009),limiting the study to individuals with stable asthma and no history oflife-threatening reaction to COX inhibitors and administering thecysteinyl leukotriene receptor 1 (Cys-LT1) antagonist montelukast to allindividuals undergoing the challenge/desensitization, the procedurecould safely be done in an ambulatory/outpatient clinic setting. Theresults of a study published in 2006 (White, Ludington, Mehra,Stevenson, & Simon, 2006), demonstrated that leukotriene modifier drugs,like montelukast, had a significant effect in protecting the lowerairways from severe reactions (P=0.004) in subjects undergoing aspirinchallenge/desensitization. Thus, montelukast substantially increases thesafety of aspirin challenge/desensitization and it is the standard ofcare to use montelukast as a pre-treatment for subjects with AERDundergoing a planned aspirin challenge/desensitization. Becausemontelukast does not inhibit CYP2C9 or CYP3A4, montelukast was notexpected to affect the elimination of ifetroban.

The primary objective of this study was to determine the safety of oralifetroban compared to placebo as measured by a ≥20% decrease in ForcedExpiratory Volume in 1 second (FEV1) compared to baseline following adose of Investigational Medicinal Product (IMP) (Study Day 1) orfollowing a dose of IMP but prior to initiation of the aspirinchallenge. Secondary objectives were: (i) to determine the safety oforal ifetroban compared to placebo as measured by peak Nasal InspiratoryFlow Rate (NIFR) compared to baseline following a dose of IMP (StudyDay 1) or following a dose of IMP but prior to initiation of the aspirinchallenge; (ii) to determine the safety of oral ifetroban compared toplacebo as measured by the change in Total Nasal Symptom Score (TNSS)compared to baseline following a dose of IMP (Study Day 1) or followinga dose of IMP but prior to initiation of the aspirin challenge; (iii) todetermine the safety and tolerability of oral ifetroban compared toplacebo as measured by treatment-emergent adverse events; (iv) todetermine the efficacy of oral ifetroban compared to placebo indecreasing the respiratory reaction to oral aspirin as measured by thechange in FEV1 compared to baseline during the aspirin challenge; (v) todetermine the efficacy of oral ifetroban compared to placebo indecreasing the respiratory reaction to oral aspirin as measured by thechange in NIFR compared to baseline during the aspirin challenge; (vi)to determine the efficacy of oral ifetroban compared to placebo indecreasing the respiratory reaction to oral aspirin as measured by thechange in TNSS compared to baseline during the aspirin challenge; (vii)to determine the efficacy of oral ifetroban compared to placebo indecreasing the respiratory reaction to oral aspirin as measured by theamount of rescue medication during the aspirin challenge; (viii) todetermine the efficacy of oral ifetroban compared to placebo indecreasing respiratory sensitivity to COX-1 inhibition as measured bythe aspirin desensitization dose level; and (ix) to determine theefficacy of oral ifetroban compared to placebo as measured by the numberof asthmatic reactions during the Treatment Period.

The main criteria for inclusion in the study were adults with a historyof physician-diagnosed stable asthma (FEV1 of at least 1.25 Liters (L)and 60% or better than predicted (calculated by spirometer based ongender, age, etc.) on two previous visits with no more than a 10%variation in those values, no increase in baseline dose of oralglucocorticoids for asthma for at least three months, and no history ofhospitalization or emergency room visits for asthma for at least theprior six months), who have a history of nasal polyposis and have ahistory of at least one clinical reaction to oral aspirin or othernonselective cyclooxygenase (COX) inhibitor with features of lower(cough, chest tightness, wheezing, dyspnea) and/or upper (rhinorrhea,sneezing, nasal obstruction, conjunctival itching and discharge) airwayinvolvement, and who are currently receiving montelukast (at least 10 mgper day, oral) or zafirlukast (at least 20 mg, twice per day, oral),with at least 1 week of therapy prior to receiving the first dose of theinvestigational medicinal product (IMP).

Subjects were allowed to enter the trial on the following medications:oral corticosteroids at a dose of ≤10 mg/day prednisone or prednisoneequivalent, inhaled/nasal corticosteroids, inhaled long-actingβ-adrenergic agonists and inhaled ipratropium; however, no modificationswere allowed during the study except for a temporary increase in thedose of oral corticosteroids if asthma worsened requiring suchintervention. Subjects were required to stop using short-actingβ-adrenergic agonists 24 hours prior, nasal decongestants andantihistamines 48 hours prior to first dose of IMP and throughout thestudy unless asthma worsened requiring such intervention.

Oral, nasal, inhaled corticosteroids and inhaled long actingbeta-adrenergic agonists and inhaled ipratropium were allowed to be usedduring the study without modification to the subject's dosing regimen ifthe subject entered the trial on such medications. It is believed thatthese medications would not mask a potential response to the aspirinchallenge. Inhaled short acting beta-adrenergic agonists, nasaldecongestants, and antihistamines were not allowed for specified periodsprior to the study and through the initiation of the aspirin challengeas these medications may mask a potential response and thus affect thestudy efficacy endpoints. Warfarin, antiplatelet, or anticoagulantmedications were prohibited 2 weeks prior to enrollment and during thecourse of the study.

The primary efficacy variable assessed was FEV1 measured by spirometry.Secondary efficacy variables included the NIFR using a Youlten meter (orsimilar), and the subject-completed questionnaire, Total Nasal SymptomScore (TNSS). Additional efficacy variables were the incidence ofasthmatic reactions, the incidence of respiratory reactions to oralaspirin, the amount of medications used to manage an aspirin-inducedreaction and the aspirin dose at which a reaction was provoked duringthe desensitization process.

The treatment period consisted of a phase A assessing safety andefficacy of IMP administered Day 1 and Day 2 followed by a phase Bassessing safety and efficacy of IMP during the aspirin challenge on Day2 and Day 3. Subjects experiencing a decrease in FEV1 of ≥20% duringphase A would not continue to phase B of the study. The follow-up periodstarted upon completion of the aspirin challenge and ended on Day 7 witha phone call to assess for safety. All subjects were required to betaking either oral montelukast or zafirlukast (at least 10 mg/day or 20mg twice per day, respectively) one week prior to the study and for theduration of the study. Ifetroban was supplied as 50-mg ifetroban sodiumcapsules and orally administered at a dose of 200 mg every 24 hours forthree consecutive days. Identically appearing placebo capsules wereprovided for blinding purposes and 4 capsules administered orally every24 hours for 3 consecutive days. The duration of IMP treatment was 3days. The study duration was 7 days.

No subject met this primary endpoint therefore all subjects continued tophase B of the study. No subject experienced a ≥20% decrease in FEV1during the aspirin challenge (phase B). At baseline, FEV1 was comparablebetween treatment groups (Table 8 and Table 10). Mean changes frombaseline FEV1 remained well below 20% throughout the treatment period inboth treatment groups. No clear trends were observed between treatmentgroups. At baseline, FEV1 was comparable between treatment groups. Meanchanges from baseline FEV1 remained well below 20% throughout thetreatment period in both treatment groups. No clear trends were observedbetween treatment groups.

Safety evaluations included spirometry, NIFR, TNSS, adverse events, &vital signs. No serious adverse events (SAE) or treatment-emergent SAEswere reported.

Additional secondary objectives included evaluating the treatment groupsfor the proportion of subjects with a ≥25% decrease in peak NIFR (nasalinspiratory flow rate) and the proportion of subjects with a ≥25%, 50%and 75% increase in TNSS (total nasal symptom score) during phase A andphase B. The results are further described in Table 4 below:

TABLE 4 Changes from Baseline in NIFR and TNSS during Phase A and PhaseB Phase A Phase B Phase C Ifetroban Placebo Ifetroban Placebo IfetrobanPlacebo No. of Subjects (%) n = 12 n = 4 n = 12 n = 4 n = 12 n = 4 NIFR≥25% decrease 2(17) 1(25) 4(33) 1(25) 5(42) 1(25) ≥25% increase 3(25) 07(58) 2(50) 9(75) 2(50) TNSS ≥25% increase 0 0 3(25) 1(25) 3(25) 1(25)≥25% decrease 1(8)  0 2(17) 0 2(17) 0 NIFR = nasal inspiratory flowrate, TNSS = total nasal symptom score; *Overall number of subjects maybe less than the sum of subjects in phase A and phase B columns since asubject that experienced an event during phase A and phase B is countedtwice. * Overall number of subjects may be less than the sum of subjectsin phase A and phase B columns since a subject that experienced an eventduring phase A and phase B is counted twice

Overall there were 6 (38%) subjects that experienced a >25% decrease inpeak NIFR, and 4 (25%) subjects that experienced a ≥25% increase in TNSSduring the study. As expected, these events occurred mainly in phase Bduring the aspirin desensitization process. Five (42%) subjectsreceiving ifetroban and 1 (25%) subject receiving placebo experienced a≥25% decrease in peak NIFR during the study. One subject in eachtreatment arm experienced a >25% decrease in peak NIFR during both phaseA and phase B. No one experienced a ≥50% or 75% increase or decrease inTNSS during the study. No subject experienced a ≥25% increase in TNSSduring phase A.

Conversely, 1 (8%) subject during phase A and 2 (17%) subjects duringphase B experienced a ≥25% decrease in TNSS but only in the ifetrobanarm. No subject on placebo experienced a ≥25% decrease in TNSS duringthe study. There were 9 (75%) subjects receiving ifetroban and 2 (50%)subjects receiving placebo that experienced a ≥25% increase in peak NIFRduring the study. These increases in peak NIFR occurred mainly in phaseB during the aspirin desensitization process. While no clear trends wereobserved in the proportion of subjects with worsening NIFR or TNSSbetween treatment groups, there is an observed trend in favor of theifetroban group toward greater improvements to NIFR and TNSS duringphase A and phase B.

No asthmatic reactions were reported or rescue medications used duringphase A prior to aspirin initiation. For this reason, all 16 subjectstreated with IMP continued to phase B. Rescue medication was onlyadministered as a result of an aspirin-induced reaction (AIR) during theaspirin desensitization process and no subject required rescuemedication outside the clinic for an asthmatic reaction throughout the7-day study period. Two (17%) subjects on ifetroban and 1 (25%) subjecton placebo did not experience an AIR during the aspirin desensitizationprocess hence no rescue medication was administered to these 3 (19%)subjects. 1 (10%) subject on the ifetroban arm experienced an AIR yetrequired no rescue medication to resolve symptoms. All 3 (100) subjectson the placebo arm that experienced an AIR required rescue medicationsand a greater number of medications on average were needed to resolvetheir symptoms compared to subjects on ifetroban that experienced anAIR. The amount of rescue medication required during the aspirinchallenge (phase B) was evaluated as a secondary efficacy endpoint.Subjects on the placebo arm required, on average, 7.33 rescuemedications to resolve an aspirin-induced reaction (AIR), while subjectson ifetroban required a mean of 2.90 rescue medications, a 2.5 folddifference. There is a trend toward fewer rescue medications in favor ofthe ifetroban group. A summary of AIRs and Rescue medication use isprovided in Table 5 below:

TABLE 5 Summary of AERD Phase 2a Data: AIRs and Rescue Medication UseIfetroban Placebo All Subjects No. of Subjects (%) n = 12 n = 4 n = 16Aspirin-induced Reaction (AIR) Yes 10 (83) 3 (75) 13 (81) No 2 (17) 1(25) 3 (19) Required Rescue Medication* Yes 9 (90) 3 (100) 12 (92) No 1(10) 0 1 (8) Total Number of 29 22  51  Rescue Medications Mean (SD)2.90 (2.02) 7.33 (3.79) 3.92 (3.04) Median*  3 9 3 Min, Max* 0, 7 3, 100, 10

There is a trend toward fewer rescue medications in favor of theifetroban group.

The incidence of the AIR provoked at each aspirin dose was evaluatedbetween treatment groups and summarized in this table. All subjects whoexperienced an AIR reacted to a provoking dose of 60 and/or 100 mg. Noreaction occurred after the 100-mg provoking dose. All initial reactionsin the placebo arm occurred at the 60-mg dose while in the ifetrobanarm, 50% of the initial reactions occurred at 60-mg and the other halfat 100-mg. One subject on placebo experienced a provoking dose reactionat 60 mg on Day 2 and another AIR on Day 3 at 100 mg. The severity ofthe 2 AIRs were comparable to one another. All other subjectsexperienced a single AIR during the aspirin desensitization process.Further information concerning AERD Phase 2a AIRs by aspirin dose ispresented in Table 6 below.

TABLE 6 Incidence of an AIR by Aspirin Dose No. of Subjects (%)*Ifetroban Placebo All AIR Subjects Aspirin Dose (mg) n = 10 n = 3** N =13 30 0 0 0 60 5(50) 3(100) 8(62) 100 5(50) 1(25)  6(46) 150 0 0 0 325 00 0 *Based on AIR population only; **1 subject experienced 1 AIR at 60mg and 1 AIR at 100 mg hence counted twice. AIR = Aspirin-inducedReaction

The incidence of the AIR provoked at each aspirin dose was evaluatedbetween treatment groups and summarized in Table 6. All subjects whoexperienced an AIR reacted to a provoking dose of 60 and/or 100 mg. Noreaction occurred after the 100-mg provoking dose. All initial reactionsin the placebo arm occurred at the 60-mg dose while in the ifetrobanarm, 50% of the initial reactions occurred at 60-mg and the other halfat 100-mg. One subject on placebo experienced a provoking dose reactionat 60 mg on Day 2 and another AIR on Day 3 at 100 mg. The severity ofthe 2 AIRs were comparable to one another. All other subjectsexperienced a single AIR during the aspirin desensitization process.

The severity of the AIRs were compared between treatment groups by thenumber of separate symptoms that manifested during the aspirinchallenge. The total number of symptoms are based on 14 AIRs thatoccurred in 13 subjects, 10 ifetroban-treated subjects and 3placebo-treated subjects. As mentioned previously, 1 subject on theplacebo arm experienced 2 AIRs. The average number of symptoms per AIRwas comparable between treatment groups. Both arms experienced abronchial reaction (<20% decrease in FEV1, wheezing, chest tightness) aspart of the AIR at a similar rate. While an upper respiratory effect(rhinorrhea, nasal obstruction, sneezing) was equally as common betweentreatment groups, an ocular manifestation seems to trend toward theplacebo arm more often than on the ifetroban arm. AIR severity in thestudy is reported in Table 7 below.

TABLE 7 Severity of an AIR by Clinical Manifestation Category/FeatureIfetroban Placebo All AIR Subjects n = 10 n = 3 N = 13 All Symptoms* 4320 63 Mean(SD) 4.3(1.34) 5.00(0.82) 4.50(1.22) Median 4 5 4 Min, Max 3.74.6 3.7 <20% decrease in 9 4 13 FEVI Mean 0.9 1 1 Upper Respiratory 2511 36 Mean 2.5 2.8 2.6 Lower Respiratory 13 5 18 Mean 1.3 1.3 1.3 Ocular5 4 9 Mean 0.5 1 0.6

In conclusion, in this clinical study, ifetroban at 200 mg/day was shownto be well tolerated and safe in subjects with a history of AERD. Therewas no increase in AEs reported in the ifetroban group compared toplacebo. All subjects completed treatment and aspirin desensitization.The primary endpoint was met; ifetroban did not cause a ≥20% decrease inFEV1. The results of this small safety study demonstrated that ifetrobanwas safe when administered to patients with AERD. In addition, resultsfrom the study suggest the symptoms of aspirin desensitization in AERDpatients may be diminished by the use of ifetroban at a dose of 200mg/day.

The primary endpoint was not met; ifetroban did not cause a ≥20%decrease in FEV1 during the course of IMP treatment or the aspirindesensitization process. Mean changes from baseline FEV1 remained wellbelow 20% throughout the treatment period in both groups with no cleartrends observed. While no appreciable difference was observed in theproportion of subjects with worsening NIFR or TNSS between treatmentgroups, there is an observed trend in favor of the ifetroban grouptoward greater improvements to NIFR and TNSS during phase A and phase B.Moreover, there is an apparent trend toward fewer rescue medications infavor of the ifetroban group and, while an upper respiratory effect wasequally as common between treatment groups, an ocular manifestationseems to trend toward the placebo arm more often than on the ifetrobanarm. Although the sample size is not sufficient to demonstratestatistically significant treatment efficacy, these data areencouraging. Larger studies with longer treatment duration are needed tomake formal conclusions about ifetroban efficacy in AERD. The results ofthis small safety study support further investigations of ifetroban at atherapeutic dose of 200 mg/day for subjects with AERD.

CONCLUSION

In the preceding specification, the invention has been described withreference to specific exemplary embodiments and examples thereof. Itwill, however, be evident that various modifications and changes may bemade thereto without departing from the broader spirit and scope of theinvention as set forth in the claims that follow. The specification anddrawings are accordingly to be regarded in an illustrative manner ratherthan a restrictive sense.

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1-19. (canceled)
 20. A method for treating and/or preventing asthma in ahuman patient, comprising administering ifetroban or a pharmaceuticallyacceptable salt thereof to the patient in a daily dose of about 200 mg,wherein the composition is administered orally.
 21. The method of claim20, wherein the daily dose is sufficient to provide a plasmaconcentration of the ifetroban or pharmaceutically acceptable saltthereof of about 1 ng/ml to about 1,000 ng/ml.
 22. The method of claim20, wherein the ifetroban or pharmaceutically acceptable salt thereof is[1S-(1α,2α,3α,4α)]-2-[[3-[4-[(Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-benzenepropanoicacid, monosodium salt (ifetroban sodium).
 23. A method of treating asymptom of aspirin desensitization in a AERD patient, comprisingadministering ifetroban or a pharmaceutically acceptable salt thereof tothe patient in a daily dose of about 200 mg, wherein the composition isadministered orally.
 24. The method of claim 23, wherein the ifetrobanis ifetroban sodium.
 25. The method of claim 23, wherein the daily doseof ifetroban treats a symptom selected from the group consisting ofnasal polyps, nasal congestion (or stuffiness), eye watering, eyeredness, coughing, wheezing, chest tightness, frontal headache,sensation of sinus pain, flushing, rash, hives, nausea, abdominalcramping, a general feeling of malaise, dizziness, difficulty breathing,and combinations of any of the foregoing.
 26. The method of claim 23,wherein the dose of ifetroban provides a plasma concentration of thethromboxane receptor antagonist of about 40 ng/ml to about 3,500 ng/ml,wherein the desired plasma concentration results in the patientexperiencing a lessening of said symptom.
 27. A method of preventing asymptom of aspirin desensitization in a AERD patient, comprisingadministering ifetroban or a pharmaceutically acceptable salt thereof tothe patient in a daily dose of about 200 mg, wherein the composition isadministered orally.
 28. The method of claim 27, wherein the ifetrobanis ifetroban sodium.
 29. The method of claim 27, wherein the dose ofifetroban provides a plasma concentration of the thromboxane receptorantagonist of about 40 ng/ml to about 3,500 ng/ml, wherein the desiredplasma concentration results in the patient experiencing a lessening ofsaid symptom.